Summary/Abstract Influenza A virus (IAV) constitutes an ongoing threat to global health. IAV infection is especially problematic in aged individuals, with estimated close to 90% IAV-associated deaths occurring in the elderly. Alveolar macrophages (AMs) are the primary lung macrophage population that are important in lung homeostasis, anti-viral immunity and tissue recovery. AMs exhibit stem-like features of self-renewal, but also can rapidly produce pro-inflammatory mediators upon stimulation, which could potentially contribute to pulmonary inflammation and injury during IAV infection. Little is known currently about the mechanisms modulating AM proliferative and inflammatory fate decisions in vivo, and the subsequent effects on tissue inflammation and recovery following IAV infection. In this application, we hypothesize that the interplay of b-catenin, HIF1-a and TCF-4 modulates AM self-renewal and inflammatory activity, thereby regulating pulmonary inflammation and tissue repair during IAV infection. Furthermore, we hypothesize that exaggerated b- catenin-HIF1-a expression dictates the aging-associated defects in AM self-renewal and function, thereby leading to severe pulmonary diseases and/or defective lung repair following IAV infection in aged hosts. Three specific Aims are proposed. Aim 1: To elucidate the associated-mechanisms by which b- catenin/HIF1-a complex modulates AM inflammatory activity and self-renewal, and subsequent effects on host diseases and recovery from IAV infection. Aim 2: To define the underlying mechanisms by which TCF- 4 regulates AM development, self-renewal and/or inflammation during homeostasis and following IAV infection. Aim 3: To determine the roles of dysregulated AM b-catenin/HIF1-a axis in contributing to aging- associated defects in AM function and regeneration, thereby causing severe IAV-associated diseases in aged hosts.